Hi Schering AG, err Bayer, err, whoever you are these days, TIE2 / VEGF Sulfoximine macrocycles I see. Those 5% cyclizations are going to need a little work… But what I really want to see is you guys resolve the enantiomers!

Hi GSK, Nice process route to VEGF -TIE2 inhibiting pyrimidines They aren’t terribly new (WO2002059110), still KP enjoys a good process application now and then. Not only do process chemists do chemistry better then the medchem folk (who’s names are on the initial applications) but nobody asks a process guy to look at the chemistry until there’s something worth making.

To Kinasepro, the real personality behind Sorafenib, is the part about how they optimized against RAF only to find out later that it was the VEGFR2 and PDGFR-b activity that was driving the efficacy. Hmm, somehow they don’t quite put it that way in the Nature Reviews DD article… Bayer has a couple PDB’s deposited for Sorafenib / BAY439006 / Nexavar (RAF; 1UWH, 1UWJ), but if you want a Urea bound to VEGF all you’ve got is 1YWN. Does this mean GSK > SKB? I tend to think US20060241149 will put an answer to that.

Yah yah 1YWN was a GSK Japan offering, while the current application is a King of Prussia SKB claim but what’s this new application all about? Mmmmm, I think you’re going to have to do better then a little TIE2 activity to make me a believer.

So I here you thinking, ‘aww, c’mon the Piperazines are cool!’ Bleh, been there done that – and the fused 5? Yah, yah I guess but hasn’t somebody already been there? I hope this is one of those applications dropped just to prevent someone else from going there… Oh, but if you’ve been wondering why you keep seeing these pyridines bearing a 2-methyl carboxamide it’s because if the pyridyl binds the hinge, you get a modest bump in activity, and:

Yours is another one of those patent applications that has Kinaspro thinking “this has got to be covered somewhere, by someone”

So did Bayer/Onyx not exemplify the N-Me Carboxamide in their earlier work?

HoHoHo-
Derek Lowe-
Wont’ ya Go-

and… umm… well… Maybe you could just walk down the hall and poke someone in the eye for me?

No, I guess there’s no need for that, they did indeed claim a handful of disubstituted pryazoles. (RAF: WO199932106, WO199932110, WO199932111, and TrkA WO2005110994), Seems to Kinasepro that these partygoers are a few years late particularly when Merck is doing what Bayer did back in 1999, and BI did first with BIRB796 and then also later with (US6492529), hell even Kirin Beer has one of these: (WO2002088110)

So Merck think’s they’ve found a way around the Bayer patent estate, and must have some kind of PK / CYP / Drug-like-property / selectivity bump that’s not obvious. They’ve got something similar going on in: WO2006040056 where they are clearly looking at one-offs of Nexavar. You have to remember these are those Crazy-evil-genius-brilliant-German Merck types…

Hmmm, so what’s new in these patents? Well, one of the claims is on TIE2, and you can tell by the Markush they are only attempting to make very narrow claims around the two Pyrazole substituents. I didn’t translate all the structure names, but it appears there are a number of furans exemplified with a handful of other R group modifications. The one example they draw a structure for:

Of note Deciphera has 2 similar applications which published in July. WO2006071940, and WO2006081034 they are labelled VEGF/PDGF/Bcr-Abl applications

And the companies with advanced Angiogenesis programs that any potential candidate has to beat: